Cognition is now recognized as the core deficit in schizophrenia and the best predictor of a patient's functional outcome. It is therefore important to understand the neurobiological basis of schizophrenia-related cognitive impairments. Currently, neurobiology is best studied in animal models. To assess cognition and its basis in the firing of neurons, we pioneered a rapidly learned two-frame avoidance task for rodent subjects. The neural correlate of two-frame cognition is "functional grouping", a population-level coordination of neural activity observed in the discharge of hippocampal neurons. These cells signal the current location of the subject. Subpopulations of these "place cells" tend to be grouped by function, signaling places in arena space or room space, but not both. This neural coordination is a direct correlate of the cognitive segregation observed in two-frame avoidance behavior. Two-frame avoidance is selectively impaired by treatment with phencyclidine (PCP), a drug that produces transient psychosis in people. In our experiments, PCP intoxication causes aberrant neural coordination of hippocampal cell firing even though basic place cell location-specific firing is normal. We hypothesize that during PCP intoxication, a failure of functional grouping is the physiological signature of the impaired two-frame cognition. We propose to test the hypothesis by recording place cell activity during the two-frame task before, during, and after PCP intoxication. The hypothesis predicts impaired neural coordination, specifically that a breakdown of functional grouping is associated with cognitive impairment. Determining whether a physiological impairment (altered neural coordination) is associated with a cognitive impairment will test the hypothesis that the core cognitive impairment in schizophrenia arises from a failure of cognitive coordination. The proposed studies will provide an experimental platform for further testing the hypothesis, and for developing novel antipsychotic therapies aimed at the neurobiological basis of the cognitive impairment in schizophrenia. PUBLIC HEALTH RELEVANCE: Cognition is the core deficit in schizophrenia, many symptoms of which are mimicked by phencyclidine (PCP) intoxication. We will study how PCP-induced alterations in the electrophysiology of cognition-related neurons could cause schizophrenia-related cognitive impairments.